CG Consult of the week 23.10.2023

Case history:

A 58-year-old male initially presented with a seize, and imaging revealed a right frontal lesion. The lesion progressed and the patient underwent craniotomy, at which time the diagnosis of glioblastoma was made. MGMT promoter methylation was detected. The patient received first line treatment consisting of radiotherapy plus temozolomide, followed by adjuvant temozolomide. The patient experienced disease progression after 5 cycles of adjuvant therapy and underwent further surgical resection. Recurrent tumor was sent for genomic profiling to aid clinical decision making.

Genomic Profiling Results:

  • EGFR G574V
  • PTEN loss
  • TERT promoter -124C>T
  • CDKN2A L78Hfs*41
  • MTAP loss
  • IDH1/2 wild type

Questions from the oncologist:

  • Unlike lung cancers with EGFR mutations, GBMs respond poorly to 1st– and 2nd-gen EGFR inhibitors. Might this patient respond to treatment with 3rd-gen inhibitors?
  • Do we expect to see mutation specific responses to EGFR TKIs?
  • Are there any novel therapeutic combinations we should be aware of?


The EGFR gene is a frequent mutational target in glioblastoma. Missense mutations that are commonly found in GBM are often located on the extracellular domain (ECD) (1), such as seen in this case. Notably, in comparison to EGFRvIII alteration (characterized by an in-frame deletion of exons 2-7 of EGFR), EGFR ECD mutations functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands, representing an intermediate phenotype between EGFR and EGFRvIII (2).

Current anti-EGFR/EGFRvIII therapeutics include small molecule TKIs, antibodies, vaccines, chimeric antigen receptor T cells and RNA-based therapies. Many chemicals or antibodies targeting EGFR/EGFRvIII are not efficient at crossing the blood–brain barrier, which limits their efficacy. Regarding EGFR TKIS, unlike EGFR mutations in the kinase domain, extracellular mutation EGFR vIII has been shown to have lower sensitivity to gefitinib and erlotinib, but retained some degree of sensitivity to afatinib (3, 4). Recent preclinical data demonstrated that Osimertinib inhibits GBM cell proliferation to a greater extent than the other EGFR-TKI(5). Moreover, it is able to penetrate the blood-brain more effectively, making it an attractive candidate for inhibiting EGFR in GBM. Recent clinical studies indicated Osimertinib response, although limited, in patients with concurrent EGFR vIII and amplification. However, the question that remains to be answered is its effectiveness against EGFR ECD point mutations in GBM(6); which has not been reported clinically. Therefore, we cannot draw a conclusion for efficacy of Osimertinib in GBM patients harboring point mutations. As noted earlier, EGFR ECD mutations functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands, which in turn result in increased exposure of the epitope to the antibody–drug conjugate. Therefore, antibody-drug conjugates targeting EGFR may be an attractive approach in targeting EGFR ECD mutation in GBM (7).  

Heterogeneous expression of oncogenic  EGFR  mutants, cooperativity of  EGFR  with itself or other RTKs and downstream signaling via bypass pathways have each been hypothesized to contribute to tumor growth and resistance to therapy. On that note, two co-alterations reported in this case are important to highlight. PTEN negatively regulates PI3K signaling downstream of EGFR, ad may preclude benefit from EGFR targeted therapy. Although co-targeting multiple components of the EGFR-PI3K-mTOR axis could be an efficient therapeutic approach in GBM, therapies blocking EGFR and downstream PI3K signaling in gliomas exhibited limited efficacy(8, 9). The RB and TP53 tumor suppressors are frequently inactivated directly or indirectly through aberrations in pathway factors such CDKN2A/CDKN2B or MDM2, such as seen in this case. Therefore, in a case like this, upfront convergent inhibition of these two pathways may be a viable option to overcome potential resistance. There are several on-going or completed clinical trials using cylin kinase inhibitors either as a single treatment or in combination with other drugs or radiotherapy(10). Of these drugs, abemaciclib has been shown to have relatively improved blood brain barrier crossing capabilities(10). Preliminary analysis of results of the Abemaciclib arm in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial suggests that abemaciclib increases PFS compared to control(11). Whether this will translate into an improvement in overall survival remains to be seen.  

Learnings From This Case: 

  • One key difference between EGFR in GBM and lung cancer is the distribution of mutations within the EGFR.
  • While EGFR plays critical roles in GBM pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors has shown limited efficacy.
  • Given the fact that osimertinib could cross the blood–brain barrier, osimertinib could be an effective drug candidate for the EGFR-negative GBM patients.
  • Deregulation of downstream molecules and upregulation of redundant RTK may bypass EGFR inhibition. Combination therapies are needed to improve outcome.



Disclaimer: all CGCotW cases are based on a true story. No resemblance to persons alive or deceased is intended or should be inferred. ©️ CGC Genomics Consults AG

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